This invention relates to the safe and efficacious transdermal administration of pergolide for, among other things, the treatment of Parkinson""s Disease. More particularly, the invention relates to novel methods, compositions, and devices for administering pergolide to a subject through a body surface or membrane over a sustained time period.
Pergolide, 8-[(methylthio)methyl]-6-propylergoline, a compound based on the ergoline ring system, is reported to be a dopaminergic agonist that also decreases plasma prolactin concentrations. When used for treating Parkinson""s Disease, pergolide is used as an adjuvant to levodopa.
U.S. Pat. No. 4,166,182, incorporated herein in its entirety by reference, describes the preparation of pergolide and its oral or parenteral administration as a prolactin inhibitor and in the treatment of Parkinson""s Disease.
German patent application DE 4240798, incorporated herein its entirety by reference, describes a pharmaceutical composition containing ergot derivatives, including pergolide, for protection of nerves. The composition may be delivered orally, sublingually, parenterally, percutaneously or nasally.
U.S. Pat. No. 4,797,405 incorporated herein in its entirety by reference, discusses stabilized pergolide oral compositions that demonstrate reduced decomposition when exposed to light.
The dopaminergic agonist effect of pergolide has resulted in its use in a variety of treatments, in addition to the treatment of Parkinson""s Disease. For example, U.S. Pat. No. 4,800,204, incorporated herein in its entirety by reference, discusses a method of controlling tobacco use by orally or parenterally administering a direct dopamine receptor agonist such as pergolide.
U.S. Pat. No. 4,935,429, incorporated herein in its entirety by reference, discusses a method of treating psychostimulant abuse by orally or parenterally administering a dopamine agonist such as pergolide.
U.S. Pat. No. 5,063,234, incorporated herein in its entirety by reference, discusses a method of inhibiting bone demineralization by administering, preferably orally, an ergot derivative, such as pergolide.
The oral administration of pergolide in the treatment of Parkinson""s Disease is initiated with 0.05 mg/day dosage for the first 2 days. The dosage is then gradually increased by 0.1 or 0.15 mg/day every third day over the next 12 days of therapy. The dosage may-then be increased by 0.25 mg/day every third day until an optimum therapeutic dosage is achieved at a range of about 1.5 to 8.0 mg/day. Generally, the daily dose is divided into three oral doses. The side effects of oral administration include, but are not limited to nausea, vomiting, dizziness and orthostatic hypotension.
The transdermal route of parenteral delivery of drugs and other biologically active agents (xe2x80x9cagentsxe2x80x9d) has been proposed for a wide variety of systemically acting and locally acting agents on either a rate-controlled or non-rate-controlled basis and is described in numerous technical publications such as the following: U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610, the disclosures of which are incorporated in their entirety herein by reference. The transdermal administration of a related compound, lisuride, for treating Parkinson""s Disease, is disclosed in U.S. Pat. Nos. 5,252,335 and 5,229,129, the disclosures of which are incorporated in their entirety herein by reference.
When first investigated in depth in the late 1960""s, the transdermal route of administration appeared to offer many advantages, particularly with respect to agents that had short half lives and therefore required frequent, repeated dosing or were subject to a high degree of first-pass metabolism by the liver when orally administered. Theoretically, the peaks and valleys in blood concentration resulting of frequent periodic doses of short half-life agents would be eliminated and replaced by substantially constant plasma concentration. This would not only improve patient compliance but also would eliminate the alternating periods of high side-effects and ineffective blood concentrations associated with period dosing. It was also thought that administering the agent through the skin directly into the blood stream would eliminate first-pass metabolism of orally administered agents.
It was initially assumed, theoretically, that any short half-life agent of high potency and skin permeability would be suitable for safe and effective transdermal administration. This assumption, however, has not been proven true.
The failure of the transdermal route to fulfill the initial expectations of its potential as an administrative portal was primarily due to the incredible variety of properties with which nature has endowed the skin to permit it to perform its function as the primary barrier to prevent the ingress of foreign substances into the body. See Transdermal Drug Delivery: Problems and Possibilities, B. M. Knepp, et al, CRC Critical Reviews and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987).
Thus, the transdermal route of administration, rather than being available to every short half-life agent of high potency and skin permeability, was found to be available only to those few agents that possess the proper combination of a host of characteristics, most of which are unpredictable, required to render the agent suitable for safe and effective transdermal administration.
The most significant of these characteristics are the following:
1. Skin Permeability. The permeability of the skin to the agent must be sufficiently high so that the agent can be administered at a therapeutically effective rate through an area of skin no greater than about 200 cm2 and preferably no greater than 50 cm2. The person-to-person variation in skin permeability at similar sites should also be considered.
2. Skin Binding. The skin beneath the transdermal delivery device has the capability of binding or dissolving a certain amount of agent. The amount of agent so bound must be supplied to the skin before the agent can be delivered into the blood stream at therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect (xe2x80x9clag timexe2x80x9d) will be observed together with corresponding delays and termination of effect upon removal of the device. The potential also exists for toxic quantities of potent agents to be contained within the skin beneath the device. Skin binding is not related to skin permeability. Agents that are highly permeable may also be highly bound causing a lag time sufficiently long as to render them unsuitable for their intended use.
3. Irritation. The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. Animal models are used to screen for irritation. Animal models, however, often produce both false positives and false negatives. There is also a wide interpersonal variation in susceptibility to irritation. An agent must be minimally irritating in a large percentage of the potential patient population in order to be suitable for safe and effective transdermal administration.
4. Sensitization. Sensitization is an allergic reaction which is induced when an agent is first applied to the skin and is elicited upon continued exposure which may occur immediately or after a long period of seemingly harmless exposure.
The sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening and burning at the site of application. More seriously, the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of the drug. If the latter occurs, the patient will be unable to take the drug by any route of administration.
Animal models are used to screen for sensitization. Animal models, however, produce both false positives and false negatives. There is also a wide variation in the allergic reaction between individuals as well as between sexes, races and skin types. It is obvious that a useful transdermal agent must be minimally sensitizing in a large percentage of the potential patient population.
5. Pharmacokinetic Properties. The half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Because blood concentrations of continuously administered agents will continue to increase for approximately five half-lives before steady-state constant blood concentrations are achieved, an agent must have a relatively short half-life to be suitable for continuous transdermal administration. The transdermal half-lives of most agents have not been determined. When half-lives of agents determined from intravenous administration are compared with half-lives determined from transdermal administration, the transdermal half-lives are generally longer but there can be wide variation in half-life between individuals based upon factors such as age, sex, health, and body type.
6. Pharmacodynamic Properties. Constant blood levels may not produce the desired therapeutic effects. For example, a therapeutic effect may only be observed at peak blood concentration obtained from bolus dosing but the peak concentration cannot be maintained because of side effects associated therewith. Also, continuous administration of many agents produces tolerance that may require either some agent-free interval or continually increasing and therefore potentially hazardous doses of the agent.
7. Potency. Although a certain degree of potency is required for transdermally administered agent to be effective, it is also possible for an agent to be too potent. As potency increases, lower blood concentrations are required and much smaller quantities are administered. Because of normal inter-individual variations and skin permeability, it may not be possible to precisely control whether a patient is receiving 1 xcexcg/hr or 2 xcexcg/hr, for example. For a highly potent agent, a 1 xcexcg/hr administration may be totally ineffective and a 2 xcexcg/hr rate fatal. Thus, the therapeutic index of an agent, which is the ratio of toxic blood concentration to the therapeutic blood concentration, becomes extremely significant. A highly potent agent may also need to have a relatively high therapeutic index in order to be suitable for transdermal administration.
8. Metabolism. One of the perceived advantages of transdermal administration was that it avoided the xe2x80x9cfirst-passxe2x80x9d metabolism of the agent by the liver that is associated with oral administration. It has now been recognized however, that the skin, not the liver, is the largest metabolizing organ in the body. Thus, although first-pass metabolism that occurs after an orally administered agent enters the blood stream can be avoided, skin metabolism, which occurs before the agent enters the bloodstream, cannot be avoided. Skin metabolism is capable of creating metabolites that are inert, toxic, or comparable in biological activity to that of the agent. An agent, to be suitable for transdermal administration, must have the metabolic properties that are consistent with its therapeutic use on continuous administration.
The above summarizes the primary characteristics that affect suitability of an agent for transdermal administration that have been recognized to date. There are undoubtedly others, some of which have not yet been recognized, and, in order for an agent to be suitable for transdermal administration, it must possess the right combination of all these characteristics, a combination of which, as illustrated by the very few drugs that are now suitable for administration from transdermal delivery devices, is quite rare and unpredictable.
It is unexpected that pergolide would be delivered through the skin at meaningful therapeutic rates either as a base or salt because, as its chemical name 8-[(methylthiolmethyl]6-propylergoline monomethanesulfonate)] indicates, it has a complex chemical structure which does not lend itself to readily permeate through biological membranes such as the skin.
Nonetheless, according to this invention, it has been discovered that pergolide can be safely and efficaciously administered transdermally to provide, among other things, treatment for Parkinson""s Disease, with a reduced incidence of side effects and improved patient compliance. In addition, the present invention provides methods for the transdermal delivery of pergolide and delivery systems for effecting the same, which are suitable for the administration of pergolide continuously through a body surface or membrane to achieve and maintain therapeutic blood plasma levels of pergolide in a patient. A particularly advantageous aspect of this invention is the ability to maintain substantially constant blood plasma levels of pergolide in a patient over extended periods of time.
As used herein, the term xe2x80x9ctransdermalxe2x80x9d intends both percutaneous and transmucosal administration, ie, passage of pergolide through intact unbroken skin or mucosal tissue into the systemic circulation.
As used herein, the term xe2x80x9cpergolidexe2x80x9d intends not only the basic form of pergolide but also a pharmaceutically acceptable salt form of pergolide.
As used herein the term xe2x80x9csaltxe2x80x9d intends, but is not limited to, pharmaceutically acceptable salts such as chlorides, acetates, sulfates, phosphates, mesylates.
As used herein, the term xe2x80x9cpergolide therapyxe2x80x9d intends all medical conditions for which pergolide is or will be indicated, including, without limitation, as a psychic energizer and in the treatment of Parkinson""s Disease, migraine, allergic responses, urticaria, hypertension, endometritis, and other conditions associated with dopaminergic agonists.
As used herein, the term xe2x80x9cindividualxe2x80x9d intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.
As used herein, the term xe2x80x9ctherapeutic effective amountxe2x80x9d intends the dose of pergolide that provides pergolide therapy, in the case of adult humans, the optimum dosage range is normally about 1.5 to 8 mg of pergolide per day.
As used herein, the phrase xe2x80x9csustained time periodxe2x80x9d or xe2x80x9cadministration periodxe2x80x9d intends at least about 8 hours and will typically intend a period in the range of about one to about seven days.
As used herein, the phrase xe2x80x9cpredetermined area of skinxe2x80x9d intends a defined area of intact unbroken skin or mucosal tissue. That area will usually be in the range of about 5 cm2 to about 100 cm2.
As used herein, the term xe2x80x9cpermeation enhancementxe2x80x9d intends an increase in the permeability of skin to pergolide in the presence of a permeation enhancer as compared to permeability of skin to pergolide in the absence of a permeation enhancer.
The present invention relates to improved compositions, devices and methods for the transdermal administration of pergolide in the treatment of Parkinson""s Disease, among other things. According to the present invention, it has been found that pergolide may be safely and efficaciously administered transdermally through a body surface or membrane at a therapeutically effective rate for a predetermined, sustained time period in order to provide an effective therapeutic result. Another aspect of the present invention is directed to the transdermal administration of pergolide together with a suitable permeation enhancer or mixture of enhancers. Therapeutic blood plasma levels of pergolide in a patient of about 100-2000 pg/ml may be achieved and maintained by the practice of this invention.
The system of the invention comprises a carrier or matrix adapted to be placed in pergolide or pergolide- and permeation-enhancing mixture-transmitting relation to the selected skin or other body site. The carrier or matrix contains sufficient amounts of pergolide or any acceptable pharmaceutical salt thereof to continuously administer to the site, over a predetermined delivery period, pergolide, at a therapeutically effective rate. In another embodiment, the carrier or matrix contains sufficient amounts of pergolide or any acceptable pharmaceutical salt thereof and the permeation-enhancing mixture to continuously coadminister to the site, over a predetermined delivery period, pergolide, at a therapeutically effective rate, and a permeation enhancer or permeation enhancer mixture.